The purpose of this study is to see whether subjects with gout who receive febuxostat or allopurinol for up to 9 years have a higher rate of serious heart and blood vessel complications (major cardiovascular events). Examples of major cardiovascular events include heart attacks, strokes, and angina (chest pain due to narrowing of the blood vessels of the heart) that need to be treated urgently with a heart operation. The overall duration of the study is dependent on the number of predefined major cardiovascular events (MACE). The length of study is expected to be approximately 9 years in order to observe the required 624 MACE. The length of study participation for each subject will vary due to the event driven study design.

The purpose of this study is to see if subjects with gout who receive febuxostat or allopurinol, once daily (QD), have a higher rate of serious heart and blood vessel complications.

First occurrence of any event in the predefined Major Adverse Cardiovascular Events Composite. [ Time Frame: At first occurrence (up to 60 Months) ] [ Designated as safety issue: Yes ]

The time from randomization to the first occurrence of any event in the predefined Major Adverse Cardiovascular Events (MACE) Composite, which includes: Cardiovascular death, Non-fatal Myocardial Infarction, Nonfatal Stroke and Unstable Angina with Urgent Coronary Revascularization.

Secondary Outcome Measures:

First occurrence of any Antiplatelet Trialists' Collaborative Event. [ Time Frame: At first occurrence (up to 60 Months) ] [ Designated as safety issue: Yes ]

The time from randomization to the first occurrence of any Antiplatelet Trialists' Collaborative Event, which includes Cardiovascular Death, Non-fatal Myocardial Infarction or Non-fatal Stroke.

First occurrence of Cardiovascular Death death. [ Time Frame: At first occurrence (up to 60 Months) ] [ Designated as safety issue: Yes ]

The time from randomization to the first occurrence of Cardiovascular Death.

Allopurinol 200 mg to 600 mg (depending on renal function), capsules, orally, once daily for up to 60 months.

Other Names:

Zyloprim

Allohexal

Allosig

Milurit

Alloril

Progout

Zyloric

Puricos

Zyrik 300

Aluron

Detailed Description:

This is a phase 3B multicenter, randomized, double-blind, active-controlled study designed to evaluate the cardiovascular (CV) safety of febuxostat compared with allopurinol in subjects with gout and significant CV comorbidities. Approximately 7500 subjects, males 50 years of age or older or females 55 years of age or older (at least 2-years post-menopausal), with gout and health problems affecting the heart or blood vessels will take part in this study at approximately 450 study centers in North America.

This study will use competitive enrollment. This means that when a target number of subjects has entered the treatment phase of the study, all further screening of subjects will be closed. The length of the study is based on an ongoing review of study results. The participation will last a maximum of 9 years and will include a maximum 28 visits to the study center. Telephone contact will be made every 2 months for subjects who have discontinued the study drug for any reason, but who are asked to continue in the study to be followed for potential cardiovascular events. This study design is called a "Time to Event Study". All study subjects will continue to be followed until enough information has been gathered to determine the overall safety of the study drug.

Gout is caused by high levels of uric acid in the body, and is associated with a broad range of conditions including heart disease, chronic kidney disease and additional risk factors like obesity and high blood pressure. Hyperuricemia, which is defined as an elevation in serum urate levels, develops into gout when urate crystals form from supersaturated body fluids and settle in joints and other organs.

People with gout may also have a higher incidence of other conditions that may be associated with hyperuricemia, gout or both. This is supported by a growing body of research demonstrating that serum urate levels are an independent predictive factor for cardiovascular disease when the effects of other risk factors have been controlled.

This study will explore the cardiovascular safety of febuxostat to determine whether the use of febuxostat is associated with a moderate increase in the risk of serious adverse cardiovascular outcomes as compared to allopurinol.

Participation will last a maximum of 5 years and will include 15 to 20 visits to the study center.

Eligibility

Ages Eligible for Study:

50 Years and older (Adult, Senior)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

The subject or the subject's legally acceptable representative signs and dates a written, informed consent form/Health Insurance Portability and Accountability Act (HIPAA) Authorization prior to the initiation of any study procedures.

The subject is male ≥50 years of age or female ≥55 years of age and at least 2-years post-menopausal.

The subject has a history of major CV or cerebrovascular disease including at least one of the following:

History of at least 6 of the following clinical, laboratory, and x-ray phenomena:

More than 1 attack of acute arthritis.

Maximum inflammation developed within 1 day.

Monoarticular arthritis.

Redness observed over joints.

First metatarsophalangeal joint painful or swollen.

Unilateral first metatarsophalangeal joint attack.

Unilateral tarsal joint attack.

Tophus (proven or suspected).

Hyperuricemia.

Asymmetric swelling within a joint on x-ray.

Subcortical cysts without erosions on x-ray.

Joint fluid culture negative for organisms during attack.

The subjects must have either:

a sUA level ≥7.0 mg/dL (≥416 μmol/L) at the Day -7 Visit OR

a sUA level ≥6.0 mg/dL (≥354 μmol/L) at the Day -7 Visit AND inadequately controlled gout (≥1 flare in the 12 months prior to screening and/or the presence of tophi).

The subject is capable of understanding and complying with protocol requirements

Exclusion Criteria:

Subjects who meet any of the following criteria will not qualify for entry into this study:

The subject has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant).

The subject has a history of xanthinuria.

The subject has received urate-lowering therapy (i.e., febuxostat, allopurinol, probenecid, etc.) or excluded medication during the screening period (beginning with Day -7).

The subject has a known hypersensitivity to febuxostat or allopurinol or any components of their formulation.

The subject has active peptic ulcer disease.

The subject has a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the first dose of study medication.

The subject had MI or stroke within 60 days prior to the Screening Visit.

The subject has ALT and/or AST values greater than 2 times the upper limit of normal (×ULN) during the Screening period.

The subject has a significant medical condition and/or conditions that would interfere with the treatment, safety, or compliance with the protocol.

The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 5 years prior to the Screening Visit or the subject consumes >14 alcoholic beverages per week.

The subject has received any investigational medicinal product within the 30 days prior to the Screening Visit and throughout the study.

The subject's estimated CLcr is <30 mL/min, where CLcr is calculated using the Cockcroft and Gault formula based on ideal body weight (IBW),

The subject is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

The subject is required to take excluded medications

The subject has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.

Inclusion Criteria:

Has a history of major cardiovascular or cerebrovascular disease including at least one of the following:

Myocardial infarction

Hospitalized unstable angina

Cardiac or cerebrovascular revascularization procedure

Stroke

Hospitalized for transient ischemic attack

Peripheral vascular disease

History of diabetes mellitus with evidence of micro- or macrovascular disease

Has a history or presence of gout defined as having one or more of the American Rheumatism Association criteria for the diagnosis of gout:

History of at least 6 of the following clinical, laboratory, and x-ray phenomena:

More than 1 attack of acute arthritis

Maximum inflammation developed within 1 day

Monoarticular arthritis

Redness observed over joints

First metatarsophalangeal joint painful or swollen

Unilateral first metatarsophalangeal joint attack

Unilateral tarsal joint attack

Tophus (proven or suspected)

Hyperuricemia

Asymmetric swelling within a joint on x-ray

Subcortical cysts without erosions on x-ray

Joint fluid culture negative for organisms during attack

Must have either:

a serum urate level greater than or equal to 7.0 mg/dL at the Day -7 Visit OR

a serum urate level greater than or equal to 6.0 mg/dL at the Day -7 Visit AND inadequately controlled gout

Exclusion Criteria:

Has secondary hyperuricemia

Has a history of xanthinuria

Has received urate-lowering or excluded medication during the screening period

Has a known hypersensitivity to febuxostat or allopurinol or any components of their formulation

Has active peptic ulcer disease

Has a history of cancer within 5 years prior to the first dose of study medication

Had a myocardial infarction or stroke within 60 days prior to the Screening Visit

Has alanine aminotransferase and/or aspartate aminotransferase values greater than 2 times the upper limit of normal during the Screening period

Has a history of drug abuse or a history of alcohol abuse within 5 years prior to the Screening Visit or the subject consumes more than14 alcoholic beverages per week

Has received any investigational medicinal product within the 30 days prior to the Screening Visit and throughout the study

Has an estimated creatinine clearance less than 30 mL/min

Is required to take excluded medications

Has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01101035